Babies born small at full term are 3-5 times more likely to contract ischemic heart disease than are heavy babies born to non-diabetic mothers. An index of fetal growth, like birth weight, is an independent risk factor more powerful than the well-known risk factors endorsed by the American Heart Association. However, the biological link between prenatal undergrowth and the propensity to contract coronary disease is elusive. This application is based on the hypothesis that intrauterine stressors such as hypoxia, hypertension and volume load will cause adaptive compensations of the gene expression pattern that will "program" the fetus for immediate survival adaptation but put the offspring at risk for adult-onset disease. During the past funding period, it was discovered that angiotensin II does not stimulate hypertrophy in vivo or in vitro, quite contrary to current dogma based on rat data. The proposal contains 3 aims designed to uncover adaptive mechanisms that are likely to bring about a life long propensity to cardiovascular disease. 1) Determine the physiological, histological, cellular and biochemical response to pressure loading and anemia in the fetus and determine the relationship between the myocyte and coronary growth. If the heart is born with too few cells, it may be failure-prone. 2) Determine the effects of fetal stressors on adult heart function and coronary conductance. If conductance is too high, the coronary endothelium may suffer from shear stress fatigue. 3) Determine the role of a specific member of the mitogen activated protein kinase (MAPK) signaling cascade (MAP kinase kinase called MEK) in regulating fetal cardiac hyperplasia versus hypertrophic growth. MEK will be blocked in both in vivo and in vitro experiments while the heart is being stimulated to grow. If MEK is blocked, pressure- induced cardiomyocyte proliferation may be prevented.